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Men get more relief than women do from painkillers like morphine, according to some studies. New research with rats hints at a possible explanation: Male rats have more receptors for the drug in a brain region involved in pain processing. Although it's not yet clear whether the same is true in humans, researchers say the study underscores the need for more research on the sex-specific effects of pain drugs.

The new study used rats in part because they exhibit a clear sex difference in morphine sensitivity, explains lead researcher Anne Murphy, a neuroscientist at Georgia State University in Atlanta. In a standard lab test, for example, both male and female rats will withdraw a paw from a hot probe in 8 or 9 seconds. After a shot of morphine, the females might tolerate the probe for another second or two, but males let the paw linger up to 20 seconds, Murphy says.

In tomorrow's Journal of Neuroscience, Murphy and colleagues report that male rats have a higher density of μ-opioid receptors in a portion of the periaqueductal gray, a brain region implicated in previous experiments as a likely site of action for opioid drugs like morphine. Injecting morphine directly into this area had a powerful analgesic effect for male, but not female, rats. When the researchers killed neurons with μ-opioid receptors by injecting a toxin bound to a morphine lookalike compound, the drug lost its analgesic effect for males, but not females. Murphy says the findings, taken together, suggest that the difference in μ-opioid receptors in the periaqueductal gray explains the sex difference in morphine sensitivity in rats.

A better understanding of underlying neurobiology could one day lead to more effective pain drugs for women, Murphy says, adding that human studies have suggested that morphine produces less analgesia--and more side effects--in women.

"This is ... a breakthrough in finding a viable mechanism of action for sex differences in opiate analgesia in animals," says Richard Bodnar, a neuroscientist at City University of New York, Queens College. Other researchers have suggested that there may be sex differences in opioid receptor number or function in pain-related areas of the brain, but "this work is the first to definitively demonstrate such differences," says neuroscientist Rebecca Craft of Washington State University, Pullman.

Could it also explain differences in opioid sensitivity in people? "There are probably some parallels," says Craft, "but it's a bit early to tell how strong the relationship is between human and animal work in this area."